Pathophysiology, diagnosis and management of cerebral venous thrombosis: A comprehensive review

Cerebral venous thrombosis is a rare cause of stroke in young mostly female adults which is frequently overlooked due to its variable clinical and radiological presentation. This review summarizes current knowledge on it risk factors, management and outcome in adults and highlights areas for future research. Females are 3 times more commonly affected and are significantly younger than males. The presenting symptoms can range from headache to loss of consciousness. However, the often-nebulous nature of symptoms can make the diagnosis challenging. Magnetic resonance imaging with venography is often the diagnostic imaging of choice. While unfractionated or low molecular-weight heparin is the mainstay of treatment, endovascular intervention with thrombolysis or thrombectomy and decompressive craniectomy may be required depending on clinical status. Nevertheless, approximately 80% of patients have a good recovery but mortality rates of −5% to 10% are not uncommon. Diagnosing cerebral venous thrombosis can be challenging but with vigilance and expert care patients have the best chance of a good clinical outcome.


Introduction
Cerebral venous thrombosis (CVT) is a relatively rare condition that comprises approximately 0.5% to 1% of all stroke and is associated with an increased mortality rate. [1,2][11][12][13][14] The risk factors for cerebral venous thrombosis are presented in Table 1.

Pathophysiology
]6] The pathophysiological changes in CVT evolve slowly over hours or days and can progress sufficiently for weeks to cause signs and symptoms of CVT.10][11][12] However, cortical collateral circulation is engaged, but intracranial hypertension subsequently leads to disruption of the blood-brain barrier and the development of vasogenic edema.][13][14]37] Figure 2 depicts the pathophysiological changes in CVT.
Superficial cortical veins drain into the SSS against the blood flow within the sinus, resulting in blood turbulence which is further aggravated by the existing fibrous septa at the inferior angle of the sinus.6]14] Furthermore, in addition to draining the cerebral hemisphere, the SSS and other dural venous sinuses also drain blood from diploic, meningeal and emissary veins.]37] The dural venous sinuses contain most of the arachnoid villi and granulations, especially in the SSS, responsible for cerebrospinal fluid absorption.39][40]

Clinical presentations
The clinical presentation of CVT is often vague and largely depends on the site and extent of the lesion, age of onset, and Risk factors of cerebral venous thrombosis. [5,12, Proth][39][40] However, about 40% of patients present with acute stroke-like syndrome within 48 hours of onset, and acute or subacute headache is the most common clinical presentation of CVT, often with a normal neurological finding.18] The clinical symptoms corresponding to each type of dural venous sinus thrombosis or overviewed in Table 2. Physicians should be alert for CVT if a patient presents with the following potential symptoms: [16,18,29,42,43] 1. Headache in a young woman who recently started taking oral contraceptive pills or in a woman of the third trimester of pregnancy.2. Persistent atypical headache in young adults.3. Stroke of unknown etiology.4. Haemorrhagic infarcts with abnormal cerebral vasculature or multiple hemorrhagic infarcts.5. Eye symptoms following a recent attack of sinusitis.
6. New onset of seizures and focal neurological signs.7. Altered level of consciousness.

Overview of diagnostic modalities
][39][40] The radiological findings of CVT can be direct visualization of venous sinus without blood flow; or maybe ischemic changes associated with the venous outflow obstruction. [3,11,18]There is no specific laboratory test that can positively exclude CVT in the acute phase of the disease, and blood tests are performed to evaluate coagulation abnormalities like an underlying hypercoagulable state, systemic infection, or an inflammatory process.][29][30] Details of the radiological findings of adult CVT are illustrated in Table 3.

CT scan and CT venography
Prompt investigation with an unenhanced CT scan of the brain is the noninvasive imaging method of choice when CVT is clinically suspected.Acute CVT may demonstrate an elongated hyper-attenuating clot known as a "cord sign," which may persist for 2 weeks and then become isodense to brain parenchyma. [18,40]Generally, a non-contrast CT scan produces an indirect sign that includes the early and late signs of venous ischemia known as sulcal effacement and diffuse parenchymal edema, ventricular effacement, or diminished differentiation between gray and white matter.However, a cerebral infarct not following a typical arterial territory, involving only a subcortical area, multiple unilateral and bilateral lesions with or without hemorrhagic changes should raise a concern about the venous origin. [3,5,12]Further, a cerebral infarct comprising multiple arterial territories should raise concerns about potential venous pathology, particularly CVT. [5,12,27]T venography (CTV) is particularly useful in acute and emergency cases and can be utilized as the initial test for assessing the patency of the deep and cortical venous system in a comatose or uncooperative patient.[8][9][10][11]18] The most frequent findings on CTV is vascular filling defects and an "empty delta sign" when the superior sagittal sinus is involved.[44,45] However, an artifact from dense cortical bones significantly reduces the diagnostic accuracy of the CT venography, and also, arachnoid granulations may protrude into the venous sinuses, mimicking filling defects by thrombus, which is another potential disadvantage of CTV imaging.[44][45][46][47] In infants, a false dense clot sign may result from the relatively high density of the blood in the sagittal sinus, and a false, empty delta sign may cause hyperdense empyema.[5][6][7][8][9][10]48] Occasionally, engorged and dilated venous malformations produce a hyperdense lesion on unenhanced CT and demonstrate a characteristic linear enhancing focus converging on a single dilated vein known as "caput medusa" or "candelabra" appearance on CT venography.[3,[5][6][7][8][9][10][11][12]18,44]

Digital subtraction angiography (DSA)
][46][47][48][49] Generally, there are filling defects in the dural venous sinuses or cortical veins, delayed venous drainage, and dilated collateral circulation.There may also be an abrupt cutoff of cortical veins with surrounding tortuous and dilated "corkscrew" collateral circulation. [5,18,29]Furthermore, DSA can identify vascular aneurysm and dural arteriovenous fistula, which might cause the formation of a false "corkscrew" sign due to sluggish venous drainage and vascular congestion. [50]evertheless, DSA has a unique ability to measure venous pressure and pressure > 10 mm H 2 O indicates a probability of parenchymal damage, which carries significant value for treatment outcome. [41,45] Treatment and guidelines

Overview of treatment protocols
Prompt diagnosis to identify and treat the associated factors, initiate anticoagulation therapy, and manage ICH should maximize the chance of a favorable outcome. [18,39,41]The management algorithm of CVT is illustrated in Figure 3.

Anticoagulation therapy
In 2011, American Heart Association-American Stroke Association guidelines proposed using full-dose unfractionated or low molecular weight heparin, followed by oral anticoagulant warfarin and acetazolamide. [11]Furthermore, in the absence of significantly powered evidence from anticoagulant therapy trials, European Stroke Organization guidelines from 2017 recommend using low molecular weight heparin except heparin-induced thrombocytopenia, or vaccine-induced immune thrombotic thrombocytopenia, decompressive craniectomy if ICH is present, and anticonvulsant medication in seizures. [18]However, neither European Stroke Organization nor American Heart Association-American Stroke Association guidelines suggested using glucocorticoids for raised intracranial pressure and cerebral edema. [11,18]The duration of oral anticoagulant treatment is usually between 3 and 12 months with a target international normalized ratio 2.0 to 3.0, but a longer duration may be required depending on the pathophysiology of CVT. [11,41,52]][50][51][52] In another study, Ferro and coworkers [53] evaluated the safety and efficacy of dabigatran and warfarin in 120 patients from December 2016 to June 2018, with a follow-up of 25 weeks.This trial observed a low risk of recurrence and bleeding (about 1% and 3% in dabigatran and warfarin group, respectively), and recanalization rates were 60% and 67%, respectively, and recommended both dabigatran and warfarin safe and effective for preventing recurrent venous thrombosis in CVT. [53]urthermore, recent small non-randomized studies by Wasay et al [54] and Nguyen et al [55] also suggested that direct oral anticoagulants (DOACs), especially rivaroxaban and dabigatran, are safe and effective as warfarin in patients with CVT in reducing the bleeding risk and improving recanalisation rates.In addition to rivaroxaban and dabigatran, Lurkin and coworkers [56] also found the efficacy of apixaban appears encouraging in CVT management despite variability in timing and dose of DOACs, similar to other study findings. [57,58]][55][56][57][58][59][60] Although DOAC do not require dose adjustment, several published papers observed that measuring plasma DOAC concentration is helpful in managing anticoagulated patients. [61,62]Furthermore, clinicians and laboratory professionals should be aware that standard hemostatic parameters, especially the activity of antithrombin III, activated Protein C and S, and fibrinogen, may be affected by DOAC, which is why prothrombin time or activated partial thromboplastin time should not be performed as standalone tests to monitor the DOAC effect.3]

Endovascular intervention
In the late 1980s, endovascular treatment for CVT was first introduced.There are 2 distinct approaches; chemical thrombolysis and mechanical thrombectomy. [14][53]64] Use of mechanical thrombectomy is increasing, presumably because interventionalists use these techniques in ischemic stroke cases and have gained more experience. [41,49,64,65]owever, a recent RCT (Thrombolysis or anticoagulation for cerebral venous thrombosis; TO-ACT) trial by Coutinho and coworkers [66] showed that endovascular treatment with standard medical care carries no significant difference in improving the clinical outcome of a severe form of CVT patients in comparison to standard medical care only.][64][65][66]

Conclusion
Cerebral venous sinus thrombosis is a rare but potentially fatal neurological condition that commonly affects young women of reproductive-age.It often remains underdiagnosed due to its nonspecific clinical presentation.A high degree of clinical suspicion is required as appropriate treatment at an early stage can improve the outcome.Low molecular weight heparin is recommended for acute treatment, while longer term treatment for 3 to 6 months is probably best undertaken with a direct oral anticoagulant.